Meningococcal Disease In Infants Research Articles

Meningococcal Vaccines: A Technological Revolution

The sneaky meningococcus is a bacterium that can cause terrible disease. Development of an effective vaccine has been extremely difficult. Meningococcal vaccines developed in the 1990s are based on the bacterial capsule, a shield that protects the bacteria and that is used to instruct our body to combat this terrible disease. These vaccines work against four types of meningococcus: A, C, W, and Y. However, they do not work against meningococcus B. Scientists had to invent a completely new way to make vaccines, reading the bacterial DNA to search for new protective components. With this new approach, named reverse vaccinology, three new bacterial components were discovered: NadA, NHBA, and fHbp. When combined with a fourth component (PorA), they form the 4CMenB vaccine. This vaccine has reduced meningococcal disease in infants by 75% in the UK. Today, 4CMenB protects children all around the world.

First immunogenicity data for the UK serogroup B meningococcal vaccination schedule in infants

In North America and Europe, serogroup B causes most cases of meningococcal disease in infants.1–3 The first serogroup B meningococcal vaccine, 4CMenB (Bexsero; GlaxoSmithKline, Rixensart, Belgium), was authorised in the EU in 2013 as a 3 + 1 schedule for infants, with three doses administered during the first year of life and a booster dose at 12 months.4 In 2015, the UK was the first country to implement a routine infant 4CMenB immunisation programme. However, cost-effectiveness and epidemiological considerations led the UK to choose a novel 2 + 1 schedule with doses at 2, 4, and 12 months of age, despite an absence of corresponding immunogenicity data.

A randomized, phase 1/2 trial of the safety, tolerability, and immunogenicity of bivalent rLP2086 meningococcal B vaccine in healthy infants

BackgroundNeisseria meningitidis serogroup B (MnB) is a major cause of invasive meningococcal disease in infants. A conserved, surface-exposed lipoprotein, LP2086 (a factor H-binding protein [fHBP]), is a promising MnB vaccine target. A bivalent, recombinant vaccine targeting the fHBP (rLP2086) of MnB was developed. MethodsThis phase 1/2 clinical study was designed to assess the immunogenicity, safety, and tolerability of a 4-dose series of the rLP2086 vaccine at 20-, 60-, 120-, or 200-μg dose levels in vaccine-naive infants when given with routine childhood vaccines. The study was to consist of two phases: a single-blind sentinel phase and an open-label full enrollment phase. During the sentinel phase, randomization of subjects to the next higher dose was delayed pending a 14-day safety review of dose 1 of the preceding dose cohort. The full enrollment phase was to occur after completion of the sentinel phase. ResultsLocal reactions were generally mild and adverse events infrequent; however, after only 46 infants were randomized into the study, fever rates were 64% and 90% in subjects receiving one 20- or 60-μg rLP2086 dose, respectively. Most fevers were <39.0°C. Only 2 subjects in the 20-μg group and 1 subject in the 60-μg group experienced fevers >39.0°C; no fevers were >40.0°C. Due to these high fever rates, the study was terminated early. No immunogenicity data were collected. This report discusses the safety and acceptability of rLP2086 in infants after one 20- or 60-μg dose. ConclusionDue to the high fever rate experienced in the 20- and 60-μg groups, rLP2086 in the current formulation may not be acceptable for infants.

Modelled evaluation of multi-component meningococcal vaccine (Bexsero®) for the prevention of invasive meningococcal disease in infants and adolescents in the UK

Neisseria meningitidis is the main cause of bacterial meningitis and sepsis in the UK, and can potentially be lethal or cause long-term sequelae. Bexsero® (4CMenB) is a new multi-component vaccine approved by the European Commission for use in individuals aged ⩾2 months. A theoretical transmission model was constructed to assess the long-term effectiveness of Bexsero compared to standard care. The model was populated with UK-specific demographic data and calibrated to ensure that the transmission dynamics of meningococcal disease in the UK were adequately simulated. The model showed the best strategy to be a routine vaccination programme at ages 2, 3, 4, 12 months and 14 years combined with a 5-year catch-up programme in toddlers aged 12-24 months and adolescents aged 15-18 years. This would lead to a 94% reduction in meningococcal cases or 150 000 cases and 15 000 deaths over a 100-year time-frame.

Quantitative Proton Nuclear Magnetic Resonance evaluation and total assignment of the capsular polysaccharide Neisseria meningitidis serogroup X

Neisseria meningitidis constitutes the main cause of meningococcal disease in infants. Serogroups A, B, C, W135, Y, and X have the higher incidence in young children and teenagers. The use of polyvalent conjugate carbohydrate-based vaccines has decreased the meningococcal infection around the world. Recently, the serogroup X has been found to be responsible of different outbreaks of meningococcal diseases, mainly in "Meningitis Belt" of Africa and the structure of the repetitive unit of the capsular polysaccharide has been confirmed through a monodimensional (13)C NMR study. No further characterization studies have been carried out, especially with the use of other nuclei. In this paper a novel method for quantification of the N. meningitidis serogroup X by proton qNMR is reported. Deep characterization of the serogroup X polysaccharide was also carried out by combination of correlation experiments involving (13)C, (1)H, and (31)P nuclei.

Ion Torrent Personal Genome Machine Sequencing for Genomic Typing of Neisseria meningitidis for Rapid Determination of Multiple Layers of Typing Information

Neisseria meningitidis causes invasive meningococcal disease in infants, toddlers, and adolescents worldwide. DNA sequence-based typing, including multilocus sequence typing, analysis of genetic determinants of antibiotic resistance, and sequence typing of vaccine antigens, has become the standard for molecular epidemiology of the organism. However, PCR of multiple targets and consecutive Sanger sequencing provide logistic constraints to reference laboratories. Taking advantage of the recent development of benchtop next-generation sequencers (NGSs) and of BIGSdb, a database accommodating and analyzing genome sequence data, we therefore explored the feasibility and accuracy of Ion Torrent Personal Genome Machine (PGM) sequencing for genomic typing of meningococci. Three strains from a previous meningococcus serogroup B community outbreak were selected to compare conventional typing results with data generated by semiconductor chip-based sequencing. In addition, sequencing of the meningococcal type strain MC58 provided information about the general performance of the technology. The PGM technology generated sequence information for all target genes addressed. The results were 100% concordant with conventional typing results, with no further editing being necessary. In addition, the amount of typing information, i.e., nucleotides and target genes analyzed, could be substantially increased by the combined use of genome sequencing and BIGSdb compared to conventional methods. In the near future, affordable and fast benchtop NGS machines like the PGM might enable reference laboratories to switch to genomic typing on a routine basis. This will reduce workloads and rapidly provide information for laboratory surveillance, outbreak investigation, assessment of vaccine preventability, and antibiotic resistance gene monitoring.

The Burden of Infant Meningococcal Disease in the United States.

In the United States, invasive meningococcal disease occurs at the highest rates in infants, with a second peak in adolescents. Early symptoms are nonspecific and may resemble viral infection, which poses a diagnostic challenge for clinicians. Moreover, the stakes of diagnostic confusion may be high because the disease may become life threatening within hours. Sequelae among survivors may be profound. In adolescent age groups, control of meningococcal disease caused by serogroups A, C, W-135, and Y rests upon universal vaccination beginning at 11–12 years of age; vaccines for serogroup B are not currently available. One 4-valent vaccine is licensed for use in infants beginning at 9 months of age but is only recommended for those at high risk. Licensure of new vaccines for infants is expected soon, and a universal immunization program is being debated. A wide range of bacteria can cause meningitis in infants and young children. In neonates aged <3 months, group B streptococcus causes most bacterial meningitis in many developed countries, followed by Escherichia coli and other Gram-negative enteric bacilli. Listeria monocytogenes can also be seen in this age group [1]. Historically, for infants and children aged <5 years, the 3 most common causes of bacterial meningitis and sepsis were Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, and Neisseria meningitidis [1]. Annual disease cases due to Hib in US children aged <5 years have been reduced by 99%, and there has been a substantial decline in pediatric invasive pneumococcal disease due to routine infant immunization programs introduced in the 1990s and 2000s [2, 3]. This leaves N. meningitidis as one of the most important causes of bacterial meningitis in infants and young children. Since 2005, the Centers for Disease Control and Prevention's (CDC's) Advisory Committee on Immunization Practices (ACIP) has recommended routine vaccination against N. meningitidis for all adolescents; recommendations for vaccination of children aged 9 months–10 years are restricted to high-risk groups [4–10]. At the present time, there are no meningococcal conjugate vaccines licensed for use in infants aged <9 months, although there are vaccines currently under review by the Food and Drug Administration (FDA). This article discusses the burden of meningococcal disease in infants in order to provide a backdrop for considering prevention strategies.

Human Lipooligosaccharide IGG That Prevents Endemic Meningococcal Disease Recognizes an Internal Lacto-N-neotetraose Structure

Antibodies that initiate complement-mediated killing of Neisseria meningitidis as they enter the bloodstream from the oropharynx protect against disseminated disease. Human IgGs that bind the neisserial L7 lipooligosaccharide (LOS) are bactericidal for L3,7 and L2,4 meningococci in the presence of human complement. These strains share a lacto-N-neotetraose (nLc4) LOS α chain. We used a set of mutants that have successive saccharide deletions from the nLc4 α chain to characterize further the binding and bactericidal activity of nLc4 LOS IgG. We found that the nLc4 α chain conforms at least four different antigens. We separately purified IgG that required the nLc4 (non-reducing) terminal galactose (Gal) for binding and IgG that bound the truncated nLc3 α chain that lacks this Gal residue. IgG that bound the internal nLc3 α chain killed both L3,7 and L2,4 strains, whereas IgG that required the nLc4 terminal Gal residue for binding killed L2,4 stains but not L3,7 strains. These results show that the diversity of LOS antibodies in human serum is as much a function of the conformation of multiple antigens by a single glycoform as of the production of multiple glycoforms. Differences in sensitivity to killing by human nLc4 LOS IgG may account for the fact that fully two-thirds of endemic group B meningococcal disease in infants and children is caused by L3,7 strains, but only 20% is caused by L2,4 stains.

From genes to vaccine: A breakthrough in the prevention of meningococcal group B disease

Although safe and effective vaccines exist for meningococcal serogroups A, C, W-135 and Y, no vaccine is available for routine use against disease caused by serogroup B (MenB). Consequently, MenB is now the most common cause of invasive meningococcal disease in Canada. MenB causes more than 80% of invasive meningococcal disease in infants and can occur at any age. The mortality and morbidity rates related to this disease are very high. Vaccine development against MenB has been hampered by the fact that MenB polysaccharide is not immunogenic in humans. Although vaccines derived from the outer membrane vesicle have been effective in controlling MenB outbreaks, such vaccines protect against the outbreak strain only. A new vaccine development strategy, reverse vaccinology, has led to the identification of genes coding for surface-exposed proteins, which are able to induce bactericidal antibodies against a broad range of MenB strains. A new vaccine containing a combination of these proteins has been tested in different age groups, in several clinical trials. The data available provide hope that control of MenB through routine vaccination will soon be possible.

Meningococcal Disease in Infants: A Potentially Difficult and Serious Diagnosis

Most children with meningococcal disease have apparent clinical signs of illness, but some do not initially present with clinical toxicity. These children with unsuspected meningococcal disease may potentially be discharged after outpatient evaluation and may deteriorate rapidly. We present the case of a 15-week-old infant boy who was brought to a private physician with symptoms of a common cold and was sent home. Three days later, his parents brought him to the hospital emergency department stating he was congested and crying a lot. He was again discharged. Another 2 days passed and his parents returned to the emergency department complaining that the infant was experiencing breathing problems. Following an examination, he was admitted to the hospital where symptoms worsened. Several hours after the infant was brought to the emergency room, he succumbed to what was later confirmed to be meningococcal disease.

A Multivalent Conjugate Vaccine for Prevention of Meningococcal Disease in Infants

AJOR PROGRESS HAS BEEN MADE IN THE DEVEL- opmentofmeningococcalvaccinesinthepast few years. Monovalent serogroup C conju- gate vaccines, shown to be immunogenic and effective in infants, have dramatically decreased the inci- dence of serogroup C disease in the countries in which they havebeenused. 1-4 Thisreductionhasoccurredamongthose immunized and, through a decrease in pharyngeal carriage of serogroup C Neisseria meningitidis, also among the un- immunizedpopulation. 5,6 Thesevaccinesdonotcoversero- group Y strains, an important cause of meningococcal dis- ease across all age groups in the United States, including infants, and are not licensed in the United States. A new tet- ravalent (serogroups A, C, W-135, and Y) conjugate vac- cine licensed for 2- to 55-year-olds is now recommended for all US adolescents, as well as other high-risk groups. 7 This recommendation was based on the fact that US ado- lescents were found to have both a relatively high inci- denceofmeningococcaldiseaseandahighcasefatalityrate. 7,8 monthsofage)anda2-doseschedule(2and4months)given along with the other vaccines in the routine immunization schedule of the respective countries. An additional group receivedtheserogroupCconjugatevaccineat2and4months ofage.At12monthsofage,somechildrenreceivedabooster dose of the study vaccine, some received a reduced dose of tetravalent polysaccharide vaccine as a probe for immuno- logic memory, and some received no additional meningo- coccal vaccine. The strengths of the study include assess- ments of multiple immunization schedules, a booster dose at 12 months of age, and immunologic memory. The primary objective of this study was to determine the proportion of children receiving 1 of the 3 primary dose schedules who had a human complement serum bacteri- cidal antibody (hSBA) titer of 1:4 or greater against each of the meningococcal serogroups included in the vaccine 1 month after the primary series. In general, an hSBA titer of 1:4 or greater is considered to be protective, although there is evidence that this assay underestimates protective immu- nity. A key finding was that at least 92% of infants who re- ceived the 2-, 3-, 4-month schedule had an hSBA titer of 1:4 orgreatertoall4serogroups.Forthe2-,4-,6-monthsched- ule, similar results were obtained for serogroups C, W-135, and Y, but the proportion of infants with an hSBA titer of at least 1:4 against serogroup A was lower at 81%. Inthe2-,4-monthprimaryseriesgroups,atleast84%had protectiveantibodylevelsto3ofthe4serogroups,with60% to 66% of infants having a protective titer against sero- group A. Following a booster dose at 12 months, at least 95% of infants developed a protective antibody level to 3 of the 4 serogroups, and 84% for serogroup A. The results for study participants who received immune challenge with a reduced dose of plain polysaccharide vaccine at 12 months, when compared with historical controls, suggest that the study vaccines induced immunologic memory, a key prop- erty of conjugate vaccines. Administration of the study vac- cine did not appear to adversely affect the immunogenicity oftheconcomitantlygivenpediatricvaccines.Moreover,re- actogenicity was similar to what would be expected for a conjugatevaccineand,amongchildrenwhoreceived2doses

Meningococcal disease presenting as bronchiolitis.

Meningococcal disease is the leading infective cause of mortality in children. Bronchiolitis and meningococcal disease share some common features. Both are seasonal diseases with epidemics in winter. A preceding history of upper respiratory tract infection is commonly present in both. We report two cases of meningococcal disease in infants whose initial presentation was suggestive of bronchiolitis. We draw attention to tachypnoea as an important but overlooked early sign of meningococcal septicaemia.